Zika virus (ZIKV) is an arthropod-borne flavivirus that has spread rapidly across the Americas with 35 countries and territories reporting active viral transmission over the past year; this epidemic has prompted the WHO to declare ZIKV a worldwide public health emergency. An effective vaccine for ZIKV would be a cost-effective intervention that limits clinical disease and controls the spread of the infection since there is no antiviral treatment available. The goal of this proposal is to design novel ZIKV vaccine candidates and conduct initial preclinical testing in newly-generated mouse models of infection and disease. In this regard, vector-based vaccine systems offer key advantages including their robust efficiency to elicit humoral and cellular immunity by mimicking infection while producing ZIKV antigens de novo. Adenovirus (Ad) vectors have emerged as one of the most promising vaccine platforms that stimulate both innate and adaptive immune responses, and have been evaluated extensively in clinical trials in the cancer vaccine and infectious disease fields. The use of simian Ad species isolated from chimpanzee and gorilla offers a unique ability to bypass pre-existing immunity to human Ad. Here, we will test whether gorilla-based Ad (GAd) vectors expressing soluble envelope (E) protein or intact subviral particles (SVPs) can elicit neutralizing humoral and cellular immune responses and protect against ZIKV infection and disease. Furthermore, we hypothesize that targeting GAd vectors specifically to dendritic cells (DCs) will facilitate direct presentation of ZIKV structural antigens and improve vaccination outcome compared to conventional Ad-based vaccine. To test our hypothesis we have developed methods to ablate native Ad tropism via genetic modifications of the viral capsid while allowing recognition of the target cell receptor and the possibility of cell-specific delivery in vivo. We showed the utility of incorporating single domain antibody (sdAb) species into viral particles for Ad targeting to cancer cell types and immature myeloid murine DCs. We propose to use GAd developed by our commercial partner GenVec, Inc., as this vector platform has greater potential for clinical translation. In support of this study, we generated a panel of sdAb candidates that bind to the DC-specific receptor Clec9A that can be exploited to induce robust T- and B-cell immune responses following vaccination. The Diamond laboratory has developed new murine models of ZIKV pathogenesis including a model of maternal-fetal transmission. These models will allow us to assess rapidly the efficacy of our different candidate vaccines. In summary, our collaborative group has the necessary reagents, technology, and expertise to develop and evaluate novel GAd-vectored ZIKV vaccine candidates using relevant animal models. We believe the translation of these results could have a significant impact on reducing ZIKV disease and spread, a beneficial effect on human health.